Robert Cuddihy

Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial

BACKGROUND Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. METHODS ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05). INTERPRETATION Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. FUNDING US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy. Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control. Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. Trial registration ClinicalTrials.gov number NCT00000620.

Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4) A 26-week double-blind study

OBJECTIVE To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P < 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P < 0.001), and −0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial

Aim:  The aim of this study was to compare the efficacy and safety of once‐daily human glucagon‐like peptide‐1 analogue liraglutide with dipeptidyl peptidase‐4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes.

Clinical Application of Incretin-Based Therapy: Therapeutic Potential, Patient Selection and Clinical Use

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide-1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve beta-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.

A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes: a randomized, controlled trial

OBJECTIVE Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the novel basal analog insulin degludec (IDeg: 70%) and insulin aspart (IAsp: 30%). We compared the safety and efficacy of IDegAsp, an alternative formulation (AF) (55% IDeg and 45% IAsp), and insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS In this 16-week, open-label trial, subjects (mean age 59.1 years, A1C 8.5%, BMI 30.3 kg/m2) were randomized to once-daily IDegAsp (n = 59), AF (n = 59), or IGlar (n = 60), all in combination with metformin. Insulin was administered before the evening meal and dose-titrated to a fasting plasma glucose (FPG) target of 4.0–6.0 mmol/L. RESULTS After 16 weeks, mean A1C decreased in all groups to comparable levels (IDegAsp: 7.0%; AF: 7.2%; IGlar: 7.1%). A similar proportion of subjects achieved A1C <7.0% without confirmed hypoglycemia in the last 4 weeks of treatment (IDegAsp: 51%; AF: 47%; IGlar: 50%). Mean 2-h postdinner plasma glucose increase was lower for IDegAsp (0.13 mmol/L) and AF (0.24 mmol/L) than IGlar (1.63 mmol/L), whereas mean FPG was similar (IDegAsp: 6.8 mmol/L; AF: 7.4 mmol/L; IGlar: 7.0 mmol/L). Hypoglycemia rates were lower for IDegAsp and IGlar than AF (1.2, 0.7, and 2.4 events/patient year). Nocturnal hypoglycemic events occurred rarely for IDegAsp (1 event) and IGlar (3 events) compared with AF (27 events). CONCLUSIONS In this proof-of-concept trial, once-daily IDegAsp was safe, well tolerated, and provided comparable overall glycemic control to IGlar at similar low rates of hypoglycemia, but better postdinner plasma glucose control.

Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin.

Diabet. Med. 28, 333–337 (2011)

Effect of intensive glycemic lowering on health-related quality of life in type 2 diabetes: ACCORD trial.

OBJECTIVE To compare the effect of intensive versus standard glycemic control strategies on health-related quality of life (HRQL) in a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS A randomly selected subsample of 2,053 ACCORD participants enrolled in the HRQL substudy was assessed at baseline and 12-, 36-, and 48-month visits. HRQL assessment included general health status (the 36-Item Short Form Health Survey [SF-36]), diabetes symptoms (the Diabetes Symptom Distress Checklist), depression (Patient Health Questionnaire [PHQ]-9), and treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire [DTSQ]). Repeated-measures ANOVA models were used to estimate change in HRQL outcomes by treatment group over 48 months adjusting for model covariates. The effects of early discontinuation of the ACCORD intensive glycemic control arm on study results were explored. RESULTS A total of 1,956 (95%) completed the self-report HRQL instrument(s) at baseline. The intensive arm had a larger decrease in SF-36 physical health component score than the standard arm (−1.6 vs. −1.1, P = 0.0345). Treatment satisfaction (DTSQ) showed larger improvement with intensive than standard (P = 0.0004). There were no differences in mean scores of the Diabetes Symptom Checklist and PHQ-9. Effects of participant transition following discontinuation of the intensive arm on HRQL were not significant. CONCLUSIONS The ACCORD trial strategy of intensive glycemic control did not lead to benefits in HRQL and was associated with modest improvement in diabetes treatment satisfaction. Thus patient acceptability was apparently not compromised with intensive and complex interventions such as those used in ACCORD.

Exenatide Once-Weekly Clinical Development: Safety and Efficacy Across a Range of Background Therapies

In patients with type 2 diabetes mellitus (T2DM), the physiologic glucagon-like peptide-1 (GLP-1) response, which is involved in glucose regulation through several mechanisms, is dysfunctional. GLP-1 receptor agonists can fill an unmet therapeutic need in the treatment of T2DM: improving glycemic control without increasing the risk of hypoglycemia (except with concomitant sulfonylureas) and reducing weight in a substantial proportion of patients. GLP-1 receptor agonists have impacted established disease treatment algorithms for T2DM. For example, in 2009 the American Diabetes Association and European Association for the Study of Diabetes revised their consensus treatment algorithm to incorporate GLP-1 receptor agonists. GLP-1 receptor agonists were originally represented by exenatide BID (ExBID), a short-acting agent requiring twice-daily injections at mealtime. The longer-acting agent liraglutide, requiring once-daily injections, recently received regulatory approval. Several other long-acting agents are in clinical development, one of which is the once-weekly formulation of exenatide (exenatide once weekly [ExQW]). This article reviews the clinical development of ExQW in the DURATION program. Patients in theses clinical trials were receiving various background treatments, ranging from lifestyle therapy to combination oral therapy, although the majority (68%) received metformin monotherapy. Specifically, safety, glycemic control, and weight were compared in patients treated with ExQW versus ExBID, sitagliptin, pioglitazone, or insulin glargine. Moreover, measures of β-cell function, cardiovascular risk, inflammation, and hepatic health were investigated. During ExQW clinical development, consistent clinical efficacy (glycosylated hemoglobin, -1.5% to -1.9%; weight, -2 kg to -4 kg) and safety data were observed in patients with T2DM treated with ExQW.

Diurnal glucose patterns of exenatide once weekly: a 1-year study using continuous glucose monitoring with ambulatory glucose profile analysis.

OBJECTIVE To use continuous glucose monitoring (CGM) to characterize diurnal glucose patterns produced by a novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration. METHODS We performed a subgroup analysis of patients with type 2 diabetes who participated in a multicenter trial (DURATION-1: Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus) comparing once-weekly with twice-daily formulations of exenatide. We are the only center to use CGM with ambulatory glucose profile (AGP) analysis to characterize glucose exposure, variability, and stability in participants assigned to exenatide once weekly. RESULTS Seven of the 303 patients in the larger study population were included in the subgroup analysis. Mean age (57.6 +/- 7 years), weight (102 +/- 17 kg), body mass index (34 +/- 3 kg/m2), and duration of diabetes (5 +/- 2 years) were comparable to characteristics of the larger study population. At 30 weeks and 52 weeks, participants treated with exenatide once weekly had a mean reduction in hemoglobin A1c level of 1.3 +/- 0.3% and 1.0 +/- 0.3%, respectively (P<.05). CGM analysis revealed a significant (P<.01) decrease in diurnal glucose exposure for 4 participants during nocturnal and daytime periods. Excess glucose exposure (compared with reference values) decreased in 6 of 7 participants, as did glucose variability. Glucose stability improved in 5 participants. The percentage of glucose values less than 70 mg/dL initially increased during the first half of the study then decreased to baseline levels by study end. CONCLUSIONS Individual glucose profiles revealed that changes in hemoglobin A1c did not consistently parallel alterations in glucose exposure, variability, and stability. AGPs provided a visual representation of improved glucose responses to exenatide once weekly.